Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity.
Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity.
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传统的抗癌药物筛选通常是在缺乏肿瘤微环境辅助细胞的情况下进行的，而辅助细胞可以深刻地改变抗肿瘤药物的活性。为了解决这一主要限制，我们开发了肿瘤细胞特异性体外生物发光成像（CS-BLI）测定。稳定表达荧光素酶的肿瘤细胞（如骨髓瘤、白血病和实体瘤）与非恶性附属细胞（如基质细胞）共培养，在基质细胞存在与不存在或药物治疗的情况下，选择性地定量肿瘤细胞的活力。CS-BLI是高通量可扩展的，可识别多种恶性肿瘤中基质诱导的化疗耐药，包括白血病细胞中的伊马替尼耐药。肿瘤细胞中基质诱导的信号与不良临床预后相关，包括活化的Akt、Ras、NF-κB、HIF-1α、myc、hTERT和IRF4的信号；生物攻击性和自我更新的标志。与传统筛选不同，CS-BLI还可以识别出对与基质相互作用的肿瘤细胞具有增强活性的药物。其中一种化合物，逆转，在弥漫性骨髓瘤骨病变的原位模型中比在传统的皮下异种移植物中表现出更强的活性。因此，使用CS-BLI可以精确筛选候选抗癌药物，以丰富临床前管道，利用潜在的治疗方法克服基质介导的耐药性，并在肿瘤-基质相互作用的背景下以合成致死方式起作用。
Conventional anti-cancer drug screening is typically performed in the absence of accessory cells of the tumor microenvironment, which can profoundly alter anti-tumor drug activity. To address this major limitation, we developed the tumor cell-specific in vitro bioluminescence imaging (CS-BLI) assay. Tumor cells (e.g. myeloma, leukemia and solid tumors) stably expressing luciferase are co-cultured with non-malignant accessory cells (e.g. stromal cells) for selective quantification of tumor cell viability, in presence vs. absence of stromal cells or drug treatment. CS-BLI is high-throughput scalable and identifies stroma-induced chemoresistance in diverse malignancies, including imatinib-resistance in leukemic cells. A stromal-induced signature in tumor cells correlates with adverse clinical prognosis and includes signatures for activated Akt, Ras, NF-κB, HIF-1α, myc, hTERT, and IRF4; signatures for biological aggressiveness and for self-renewal. Unlike conventional screening, CS-BLI can also identify agents with increased activity against tumor cells interacting with stroma. One such compound, reversine, exhibits more potent activity in an orthotopic model of diffuse myeloma bone lesions than in conventional subcutaneous xenografts. Use of CS-BLI, therefore, enables refined screening of candidate anti-cancer agents to enrich preclinical pipelines with potential therapeutics that overcome stroma-mediated drug resistance and can act in a synthetic lethal manner in the context of tumor-stromal interactions.
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